Multicomponent crystal forms for drugs with poor solubility, such as orotic acid (OA), can potentially promote dissolution behavior and bioavailability. Herein an affinity prediction was carried out to predict the formation of multicomponent crystal forms between OA and 41 coformers. Amino acids were selected as coformers to solve the solid-state solubility problem of OA. Six new multicomponent crystal forms, including five salts and one salt hydrate, were characterized and confirmed by powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis. Spectroscopic techniques, such as Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy, were used to validate the cocrystal/salt dichotomy. In the crystal packing, all salts exhibit N+–H···O– intermolecular interactions, which is well explained by molecular electrostatic potential surfaces. Finally, a powder dissolution study was conducted. The powder dissolution of all salts presented a higher apparent solubility (1.15–1.32 times) and a faster dissolution rate in comparison to those of OA, which is ascribed to the strength of the crystal lattice and the solvation of components.

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